Anthocyanins are glycosides of flavylium salts. Each anthocyanin thus comprises three component parts: the hydroxylated core (the aglycone); the saccharide unit; and the counter ion. Anthocyanins are naturally occurring pigments present in many flowers and fruit and individual anthocyanins are available commercially as the chloride salts, e.g. from Polyphenols Laboratories AS, Sandnes, Norway.
As individual compounds, anthocyanins have been proposed for use as antioxidants (e.g. as free radical scavengers) for treatment of the vascular system.
Uses of anthocyanins in lowering C-reactive protein levels, treating or preventing type 2 diabetes, treating or preventing cardiovascular problems, and lowering the risk of adverse side effects of hormone replacement therapy, are disclosed in international patent application publication No. WO 04/096240.
Anthocyanins occur naturally in various fruits and vegetables. Particularly suitable sources for anthocyanins are fruits such as cherries, bilberries, blueberries, blackcurrants, redcurrants, grapes, cranberries, strawberries and apples, and vegetables such as red cabbage. Bilberries, in particular Vaccinium myrtillus, and blackcurrants, in particular Ribes nigrum, are especially suitable. The berries of V. myrtillus contain fifteen monosaccharide anthocyanins, namely the aglycone:saccharide combinations of cyanidin, peonidin, delphinidin, petunidin and malvidin with glucose, galactose and arabinose. The currants of R. nigrum contain four anthocyanins, namely the 3-glucosides and 3-rutinosides of cyanidin and delphinidin.
Anthocyanin-containing products may be prepared from such natural sources. International patent application publication No. WO 03/039569 discloses a method of preparing anthocyanin-containing products. This method can be applied to extracts from fruit or vegetables.
Rather than obtaining anthocyanins or anthocyanin-containing compositions from natural sources, they may be prepared by synthetic methods. Synthetic methods provide an alternative route to extraction from natural sources and may be preferable for the production of large quantities of specific anthocyanins. Synthesis of anthocyanins may also ease the regulatory process and/or avoid supply problems if a specific anthocyanin or mixture thereof is to be used as a medicament. Thus, a synthetic route may allow greater control of the purity or exact composition of a potential pharmaceutically active product.
Known synthetic routes to flavylium ions may involve the coupling together of two halves, the so-called “Eastern” and “Western” portions of the molecule (see for example, D. D. Pratt, R. Robinson, J. Chem. Soc. 1923, 745; T. J. Nolan, D. D. Pratt, R. Robinson, J. Chem. Soc. 1926, 1968; S. Murakami, R. Robinson, J. Chem. Soc. 1932, 1537; W. Bradley, R. Robinson, J. Chem. Soc. 1932, 1541; L. Reichel, H. W. Doering, Justus Liebigs Ann. Chem., 1957, 606, 137; A. R. Katrizky, P. Czerney, J. R. Levell, W. Du, Eur. J. Org. Chem. 1998, 2623; C. Michaelidis, R. Wizinger, Helv. Chim. Acta 1951, 34, 1761; K. Kokkinos, R. Wizinger, Helv. Chim. Acta 1973, 56, 983; K. Kokkinos, R. Wizinger, Helv. Chim. Acta 1973, 56, 985; K. Kokkinos, R. Wizinger, Helv. Chim. Acta 1973, 56, 987; F. Herstein, S. Von Kostanecki, Ber. Dtsch. Chem. Ges. 1899, 32, 318; A. Roque, C. Lodeiro, F. Pina, M. Maestri, R. Ballardini, V. Balzani, Eur. J. Org. Chem. 2002, 2699; and R. A. McCelland, G. H. McGall, J. Org. Chem. 1982, 47, 3730; O. Dangles, A. El Hajji, Helv. Chim. Acta 1994, 77, 1595).
The “Eastern” and “Western” portions of anthocyanins are terms in the art to the synthetic organic chemist.
For example, anthocyanins may be prepared by the following general method as illustrated in Scheme 1 in accordance with the pioneering work of Sir Robert Robinson (the first total synthesis of cyanidin 3-O-β-glucopyranoside chloride as reported in S. Murakami, A. Robertson, R. Robinson, J. Chem. Soc. 1931, 2665 and the first total synthesis of delphinidin 3-O-β-glucopyranoside chloride, as reported in T. M. Reynolds, R. Robinson, J. Chem. Soc. 1934, 1039. The first anthocyanin to be synthesized by total synthesis was pelargonidin 3-O-β-glucopyranoside chloride (A. Robertson, R. Robinson, J. Chem. Soc. 1928, 1460). To the best of the inventor's knowledge, the last total synthesis of anthocyanins was reported by O. Dangles, A. El Hajji, Helv. Chim. Acta 1994, 77, 1595).

However, known methods for preparing anthocyanins result in poor yields. Robinson used the Koenigs-Knorr reaction to prepare “Eastern” intermediates. This reaction requires the use of extremely dry conditions, results in low yields, and is not easily adaptable for use on a large scale. An attempt by the inventor of the present invention to synthesize an “Eastern” intermediate similar to one prepared by Robinson proceeded in only 8% yield (Scheme 2). This involved coupling 2-hydroxy-3′,4′-diphenylmethylenedioxyacetophenone with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide.

Other known methods for preparing anthocyanins suffer from different drawbacks. For example, the Clemmensen reduction of rutin to give the corresponding anthocyanin, cyanidin 3-rutinose chloride (keracyanin), requires the use of toxic zinc amalgam (M. Elhabiri, P. Figueiredo, A. Fougerousse, R. Brouillard, Tetrahedron Lett., 1995, 36, 4611).